This invention relates to the fields of pharmaceutical and organic chemistry, and provides novel intermediates which are useful in the synthesis of tetrahydropyrido[2,3-d]pyrimidine (tetrahydrofolic acid) antimetabolites of the antifolate type. This invention also relates to processes for the preparation of such intermediates.
Substituted pyrido[2,3-d]pyrimidine-based antifolates have been used for a number of years as chemotherapeutic agents in the treatment of cancer. One such drug, methotrexate, is now one of the most widely used anticancer drugs; and many other compounds in the folic acid family have been synthesized, tested and discussed in the chemical and medical literature. The compounds have various activities at the enzymatic level; they inhibit such enzymes as dihydrofolate reductase, folate potyglutamate synthetase, glycinamide ribonucleotide formyltransferase and thymidylate synthase.
More particularly, a tetrahydrofolic acid antitumor agent, 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF/lometrexol), inhibits glycinamide ribonucleotide transformylase (GARFT), an enzyme required in the initial stage of de novo purine biosynthesis. See, U.S. Pat. No. 4,685,653; J, Med, Chem., 28:914 (1985). However, the process for preparing lometrexol, and analogs thereof, has not been optimized.
The present invention provides a novel intermediate, and processes thereto, which help to optimize the process for preparing tetrahydrofolic acid derivatives.